This application is a 371 of PCT/AU98/00207, filed Mar. 26, 1998.
The present invention relates to a method of mediating the effects of light on melatonin rhythmicity and, accordingly a method of mediation of circadian rhythms. The invention further relates to a method of treatment of conditions associated with dysfunctional or arrhythmic melatonin production.
Daily, or circadian, rhythms are common to all eukaryotic biological organisms, including humans. Circadian rhythms help coordinate a number of functions, most notably sleeping patterns.
There is a growing awareness for the human population of the involvement of circadian rhythms, and consequent state of sleepfulness or wakefulness, on human health, safety and productivity. It is recognised that physical and mental abnormalities associated with night work or shift work and rapid travel across time zones involve disruptions of the human circadian clock system and the sleep-wake cycle controlled by it. Other health problems associated with a disrupted circadian rhythm include insomnia, some forms of depression, and Seasonal Affective Disorder (SAD). The ability to manipulate circadian rhythms is therefore desirable and offers benefits to those industries with a need for shift work, to long distance travellers and to other sufferers from the various illnesses associated with disrupted circadian rhythms.
In addition, circadian rhythms are of importance in the control of seasonal breeding cycles of a number of economically important animals such as horses, sheep, deer and goats. A greater control of these breeding seasons provides breeders with increased flexibility and the potential for increased productivity and/or profit.
It is now well established that the hormone melatonin plays a crucial role in the maintenance of circadian rhythms. Melatonin is known to be produced in the pineal gland only during hours of sleep/darkness, the production ceasing with daybreak. The cycle of melatonin production and the cessation of production therefore underlie the circadian rhythm and because of this, crude attempts to control or alter the rhythm by administering melatonin have been made.
It is further known that the area of the hypothalamus known as the suprachiasmatic nucleus (SCN) coordinates, amongst other rhythmic physiological processes, the production of melatonin in the pineal gland. It is thus the endogenous rhythmicity of the SCN, modulated in time by retinally perceived light, that is responsible for the precise timing of the melatonin rhythm. The neural pathways of the SCN are a key factor in the control of pineal melatonin production.
The current understanding is that there are three pathways by which light influences SCN function, and thus ultimately melatonin secretion. The first is the retino-hypothalamic tract which utilises neurons originating in retinal ganglion cells and projecting to the ventro-lateral SCN area. The second pathway is an indirect multi-synaptic pathway which involves retinal ganglion cell projections to the intergeniculate leaflet and then via neurones returning to the SCN. A third, more controversial projection involves a retinal-raphe nucleus pathway which incorporates a raphe-SCN projection. Whereas the first two projections are known to exist in both hamsters and rats, the latter pathway has not been found in hamsters.
The retino-hypothalamic tract appears to use excitatory amino acids (EEAs; eg, aspartate, glutamate) as the major neurotransmitters, and it has been suggested that EEAs might mediate the effects of light at the level of the SCN. However, experiments conducted by the present inventor lead to the conclusion that EEAs are not involved in mediating the effects of light on the SCN of rats, or that an alternative pathway exists in parallel with the retino-hypothalamic tract.
Further investigations made by the present inventor have followed from the notion that serotonergic pathways may be involved in circadian rhythmicity, and the present invention is predicated on the discovery that a serotonergic pathway utilising 5-HT2c receptor in the SCN is involved in mediating the effects of light on melatonin rhythmicity.
Therefore, according to one aspect of the present invention, there is provided a method of mediating the effects of light on melatonin rhythmicity or mediating the effects of cicadian rhythms in mammals in need of such treatment comprising administering a therapeutically effective amount of a compound, or compounds, having a high affinity for a serotonin 5-HT2c receptor.
Advantageously, the timing of administration of the compound can be predetermined to coincide with an appropriate phase on an existing circadian rhythm to produce a selected mediation of the cycle.
It has been found that the administration of compounds having a high affinity for the serotonin 5-HT2c receptor site are able to phase shift an existing circadian rhythm by inhibiting melatonin production and causing delays in the onset of melatonin production for up to 3 nights following administration. In addition, it is known that core body temperature follows a circadian rhythm which can also be mediated by the administration of compounds, having a high affinity for a serotonin 5-HT2c receptor.
Among the compound or compounds having a high affinity for the 5-HT2c serotonin receptor are the following, although it should be stressed that the invention is not limited to these compounds:
(+/xe2x88x92)-1-(4-iodo-2,5-dimethoxy-phenyl)-2-aminopropane, (DOI); 1-(3-chlorophenyl)piperazine, (mCPP) and compounds which are metabolised to mCPP (desyrel, nefazodone and tradozone); 1-(xcex1,xcex1,xcex1-trifluoro-m-tolyl)-piperazine, (TFMPP); (dl)-4-bromo-2,5-dimethoxyamphetamineHCl, (DOB); (dl)-2,5-dimethoxy-4-methylamphetamine HCl, (DOM); mesulergine; ritanserin; (clozapine; loxapine; R(+)-2-di-n-propylamino-8-hydroxy-1,2,3,4-tetrahydronapthalene, (SCH 23390); tiosperone; fluperlapine; rilapine; chlorpromazine; ketanserin; risperidone; cis-fluphenixol; quipazine; 6-chloro-2-(1-piperazinyl)pyrazine, (MK-212); spiperone; metergoline; methysergide; 6-methyl-1-(1-methylethyl)-ergoline-8-carboxylic acid (8xcex2)-2-hydroxy-1-methylpropyl ester(Z)-2-butenedioate(1:1), (LY-53857); methiothepin; cyproheptadine; perenpirone; N-(1-methyl-5-indolyl-N-(3-pyridyl) urea, (SB-200646); pitozifen; 2-(2-dimethylaminoethylthio)-3-phenylquinoline, (ICI-169-369); lisuride; methergine; piremperone; ergometrine.
Preferably, the serotonin 5-HT2c receptor active compound is selected from the, group consisting of: DOI, mCPP, TFMPP, MK-212, and quipazine. More preferably still, the serotonin 5-HT2c receptor active compound is DOI.
Preferably, the serotonin 5-HT2c receptor active compound is administered at a concentration of 0.005-25 mg/kg of body weight.
In further aspects of the present invention it is possible to administer the therapeutically effective amount of a serotonin 5-HT2c receptor active compound or compounds in a timed manner, optionally in combination with melatonin to thereby further mediate an existing circadian rhythm, and in one form the invention may comprise a pharmaceutical package containing one or more therapeutically effective doses of a serotonin 5-HT2c receptor active compound or compounds, the package containing suitable indicia for calculating the dosage and timing of administration of the dosage to produce a selected mediation of the melatonin production cycle. The invention further comprises a method of treatment of the following conditions in mammals by administration of a therapeutically effective amount of a serotonin 5-HT2c receptor active compound; advanced phase sleep insomnia, delayed sleep phase insomnia, Seasonal Affective Disorder, Shift Work dysrhythmia, jet-lag, and the control of physiological systems which respond to light, and the control of seasonal breeding cycles of animals. Typically, the mediating effect on the circadian rhythms can be monitored experimentally in rats from an analysis of the output of the pineal gland via the urinary metabolite of melatonin, 6-sulphatoxymelatonin (aMT.6S) following drug treatment to provide information on the transmitters mediating the effects of light. Experimentally rats are maintained in metabolism cages and fed a high protein liquid diet to promote urine flow during the night. Urine produced is continuously pumped out of the urine collection vessels by a peristaltic pump and deposited in vials in a multi-channel fraction collector. Using this arrangement, hourly samples can be obtained non-invasively for more than four days. It can be demonstrated that light presented between 2-8 hours after dark onset (ie between ZT14 and ZT20) results in the acute suppression of aMT.6S excretion and causes the normal nocturnal increase to be delayed by several hours on subsequent nights. In subsequent studies, it has been found that light pulses of low intensity (2 lux) and short duration (1 minute) have this dual effect of acute suppression and phase delay when presented at CT18, that is 6 hours after subjective lights out in animals maintained in continuous darkness. The effects of administering an appropriate dose of an agonist compound having a high affinity for a serotonin 5-HT2c receptor provokes the equivalent of these light effects on pineal rhythmicity and causes a dose dependent acute suppression in melatonin production and a delay of up to several hours in the on set of production in subsequent nights. Thus, an existing circadian rhythm is delayed by the administration of the compounds to the extent of the delay in on set of production of melatonin. Alternatively, administration of a serotonin antagonist having a high affinity for the 5-HT2c receptor would block the phase advancing or delaying effects of a light pulse on the melatonin rhythm.
Additionally, by administering a plurality of doses of an appropriate 5-HT2c receptor active compound, or mixture of compounds at intervals, it is possible to induce a phase advance of a circadian rhythm. Thus, by administering repetitive doses, for example on two or more successive days just before subjective dawn (ie in the hours ZT21-ZT24) it will be possible to produce a phase advance of several hours. The administration of doses can be maintained until the desired mediated rhythm is established.